During the past two decades several radioactive probes have been developed for scintigraphic imaging of inflammation. Scintigraphic detection is based on local physicochemical changes and is consequently superior to radiological techniques, including X-ray computed tomography, magnetic resonance imaging and ultrasonography, which rely on anatomical changes. Scintigraphic techniques can, for example, be used to detect early inflammation, when anatomical structures have not yet been altered. Two types of radioactive probes are currently used for scintigraphic imaging of inflammation. One type of probe shows increased extravasation at the site of inflammation due to the locally enhanced vascular permeability. The second probe utilizes the diapedesis and chemotaxis of leukocytes, namely radiolabeled white blood cells and radiolabeled monoclonal antibodies or radiolabeled peptide ligands that target, respectively, leukocyte antigens or receptors. All of these probes are radiolabeled with a single photon-emitting isotope and therefore used with single photon emission computed tomography (SPECT). While PET and SPECT detect distribution of radioactive probes, PET has a much greater sensitivity and resolution than SPECT. In addition, PET has the ability to measure the concentration of radioactive probes quantitatively. No PET probes specific for imaging inflammatory processes are currently available. [18F]Fluorodeoxyglucose ([18F]FDG) has been used to image inflammation using PET [For example, see: (a) Sugawara, Y.; Braun, D. K.; Kison, P. V.; Russo, J. E.; Zasadny, K. R.; Wahl, R. L. “Rapid detection of human infections with fluorine-18 fluorodeoxyglucose and positron emission tomography: preliminary results.” Eur. J. Nucl. Med. 1998, 25, 1238-1243. (b) Stumpe, K. D.; Dazzi, H.; Schaffner, A.; von Schulthess, G. K. “Infection imaging using whole-body FDG-PET.” Eur. J. Nucl. Med. 2000, 27, 822-832.]. [18F]FDG accumulates at the site of inflammation because of the increased glucose uptake of infiltrated granulocytes and tissue macrophages. However, the glucose uptake occurs in any cell type with high glycolytic activity. In addition, [18F]FDG uptake at the site of inflammation is affected by serum glucose levels and by conditions such as diabetes mellitus. These factors limit the use of [18F]FDG as a PET imaging probe specific for inflammation.
Since the discovery of cyclooxygenase-2, an inducible form of cyclooxygenase involved in inflammation, a number of reports have appeared on the development of cyclooxygenase-2 selective inhibitors. In 1995, McCarthy et al. reported the 18F-labeling of a cyclooxygenase-2 selective inhibitor, SC-58125, and its in vivo imaging in a baboon (McCarthy, T. J., et al. (1995) J. Nucl. Med. 36, 49P; see also McCarthy, T. J., et al. (2002) J. Nucl. Med. 43:117-124). However, SC-58125 suffers from a relatively low cyclooxygenase-2 affinity (COX-2 IC50=0.10 μM), as well as a long plasma half-life (221 hours in male rat), which are unfavorable properties for PET imaging probes. See T. D. Penning et al. J. Med. Chem. 1997, 40, 1347-1365. Consequently, 18F-labeled SC-58125 has never been further investigated as a PET imaging probe for cyclooxygenase-2 detection. Very recently, de Vries and Vaalburg reported the radiochemical synthesis of 18F-labeled COX-2 selective inhibitor, DuP-697, and its desbromo derivative by a 18F for 19F exchange reaction as potential PET imaging probes for COX-2 [E. F. J. de Vries, W. Vaalburg J. Labelled Cpd. Radiopharm. 2001, 44 (Suppl 1), S933-S935]. DuP-697 is however less potent than SC-58125 (prostaglandin synthesis IC50>1 μM). See K. R. Gans et al. J. Pharmacol. Exp. Ther. 1990, 254, 180-187. Furthermore, the 18F for 19F exchange reaction is not suitable for the synthesis of 18F-labeled compounds with high specific activity (i.e., ˜103-104 Ci/mmol) required for imaging probes designed to interact with molecular recognition sites, such as COX-2-selective inhibitors that interact with the substrate-binding site of COX-2.
Cyclooxygenase-2 selective agents that are useful as imaging probes would facilitate the in vivo imaging of a variety of inflammatory processes. In addition, novel cyclooxygenase-2 selective agents that selectively inhibit cyclooxygenase-2 activity could be used to treat physiological disorders in which cyclooxygenase-2 is elevated.